Bipolardisorder(BD)isacommonmentalillnessthataffects1?2%oftheworld'spopulation,including>100,000 veterans,causingseveremoodsymptoms,volumetricoflossofbraingraymatter,andelevatedratesofsuicide.Among itssymptoms,BDisassociatedwithdisrupteddaily24hrrhythms(circadianrhythms)insleepandactivity.However, duetosimilaritiesandoverlapwithotherpsychiatricsyndromes,itiscommonlymisdiagnosedandtreatmentdelaysare frequent.LithiumisanexcellenttreatmentforBD,but30?50%oflithiumtreatedpatientsfailtorespondfullyto treatmentand/orsufferside?effects.Thesefactorscauseneedlessdelaysfromunsuccessfultreatment,increasingcost, disability,andextendingthewindoworriskforsuicide.Becauseofthesechallenges,newtechniquestodiagnoseBD, andmorerapidlyidentifylithiumresponderswouldbeoftremendousclinicalutility.Whilethesuprachiasmaticnucleus ofthehypothalamusisthe?masterclock?forcircadianrhythms,thegenesthatcontrolcircadianrhythms(?clock genes?)arefunctionalinperipheraltissuesandcanbestudiedinculturedskincells(fibroblasts)frompatients.Lithium haseffectsoncircadianrhythmsinfibroblasts,alteringtheexpressionofclockgenes,increasingrhythmamplitude (intensity)andlengtheningperiod(thedurationbetweencycles).Usingbioluminescentreportergenes(Per2::luc),one canaccuratelystudythecircadianclockintissuesfromBDpatientsandcontrols.Usingthisapproach,wehaveidentified clockgeneabnormalitiesinBD,andcircadianrhythmdifferencesinperiodthatdistinguishlithiumresponsiveandnon? responsiveBDpatients.Inotherstudies,wehaveidentifiedneurotrophinsaspharmacogeneticindicatorsoftherapeutic responsetolithiuminBDpatients.Interestingly,neurotrophinsareexpressedrhythmicallyunderthecontrolofthe circadianclock.Inthisproposal,weaimtoextenduponthisworkandsynthesizetheseobservationsto1)Establisha cellularmodeloflithiumresponsiveBDbasedoncelldeathandprotectionbylithium2)Determinetheeffectof circadianrhythmamplitudeonregulatingthevulnerabilityofneuronstooxidative/excitotoxiccelldeathand3) Determinetherelationshipbetweencircadianperiodandlithiumresponsiveness,focusingonneuroprotectionby lithium.Themethodologicalapproachismolecularandcellbased,usinggenetic(siRNAknockdown)and pharmacologicalmeanstomanipulatecircadianamplitude,periodandoverallrhythmicityinhumanfibroblasts,stem? cellderivedinducedneurons,andimmortalizedmousehippocampalneurons.Followingthesemanipulations, differencesincircadianrhythmparameters(amplitude/period)andcelldeathwillbemeasuredintheabsenceand presenceoflithium.Itisexpectedthatcellsfromlithium?responsivepatientswillbemoreabletobenefitfromthe protectiveeffectsoflithiumincelldeathassays.Furthermore,short?periodandhighamplituderhythmsincellswilllead togreaterresilienceunderconditionsofexcitotoxic/oxidativestress.Analysiswillbeconductedusingcurvefitting methodstomeasurerhythmsandunivariatestatisticalanalysestoidentifymeandifferencesincellsurvivalbasedon phenotypicorcircadianparameters.Whencomplete,thesestudiesmayprovidemechanisticinsightsintothe vulnerabilityfactorsunderlyingBD,andmolecularmechanismsunderpinninglithium'smodeofactionintreatingBD.By understandingtheseaspectsofBD,itmaybepossibleinthefuturetodeveloppredictorsoftreatmentresponse, diagnostictools,ornewtreatmentinterventionsbasedontheseresults.